p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells

Browne, Andrew; Göbel, Andy; Thiele, Stefanie; Hofbauer, Lorenz C.; Rauner, Martina; Rachner, Tilman D.

doi:10.1038/cddis.2016.32

Cited by 45 publications

(35 citation statements)

References 52 publications

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“…Several studies have identified p38g inhibitors as promising therapeutic agents for many tumor types; such as colon (Yin et al, 2015), prostate (Browne et al, 2016), esophageal (Zheng et al, 2016), and breast cancers (Qi et al, 2015). In addition to activity against CTCL, the p38g inhibitor we identified, F7/PIK75, also shows activity against cells derived from several types of cancers, including prostate, ovarian, and breast cancers (see Supplementary Table S2).…”

Section: Discussionmentioning

confidence: 89%

Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma

Zhang

Nam

et al. 2018

Journal of Investigative Dermatology

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Current cutaneous T-cell lymphoma (CTCL) therapies are marked by an abbreviated response, subsequent drug resistance, and poor prognosis for patients with advanced disease. An understanding of molecular regulators involved in CTCL is needed to develop effective targeted therapies. One candidate regulator is p38γ, a mitogen-activated protein kinase crucial for malignant T-cell activity and growth. p38γ gene expression is selectively increased in CTCL patient samples and cell lines but not in healthy T cells. In addition, gene silencing of p38γ reduced CTCL cell viability, showing a key role in CTCL pathogenesis. Screening p38γ inhibitors is critical for understanding the mechanism of CTCL tumorigenesis and developing therapeutic applications. We prioritized a potent p38γ inhibitor (F7, also known as PIK75) through a high-throughput kinase inhibitor screen. At nanomolar concentrations, PIK75, a multiple kinase inhibitor, selectively killed CD4 malignant CTCL cells but spared healthy CD4 cells; induced significant reduction of tumor size in mouse xenografts; and effectively inhibited p38γ enzymatic activity and phosphorylation of its substrate, DLGH1, in CTCL cells and mouse xenografts. Here, we report that PIK75 has a potential clinical application to serve as a scaffold molecule for the development of a more selective p38γ inhibitor.

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Section: Discussionmentioning

confidence: 89%

Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma

Zhang

Nam

et al. 2018

Journal of Investigative Dermatology

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“…4 A and 4 B). In addition, anisomycin, a chemical activator of p38 [34] , partially reversed the effects of chloroquine on oxalate-induced p38 phosphorylation, cell viability inhibition, LDH release, ROS generation and membrane potential losses, whereas had no significant effect on chloroquine-mediated ratio of LC3 II/LC3 I ( Figs. 4 C- 4 G).…”

Section: Resultsmentioning

confidence: 99%

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney

et al. 2018

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Hyperoxaluria-induced oxidative injury of renal tubular epithelial cell is a casual and essential factor in kidney calcium oxalate (CaOx) stone formation. Autophagy has been shown to be critical for the regulation of oxidative stress-induced renal tubular injury; however, little is known about its role in kidney CaOx stone formation. In the present study, we found that the autophagy antagonist chloroquine could significantly attenuate oxalate-induced autophagy activation, oxidative injury and mitochondrial damage of renal tubular cells in vitro and in vivo, as well as hyperoxaluria-induced CaOx crystals depositions in rat kidney, whereas the autophagy agonist rapamycin exerted contrasting effects. In addition, oxalate-induced p38 phosphorylation was significantly attenuated by chloroquine pretreatment but was markedly enhanced by rapamycin pretreatment, whereas the protective effect of chloroquine on rat renal tubular cell oxidative injury was partly reversed by a p38 protein kinase activator anisomycin. Furthermore, the knockdown of Beclin1 represented similar effects to chloroquine on oxalate-induced cell oxidative injury and p38 phosphorylation in vitro. Taken together, our results revealed that autophagy inhibition could attenuate oxalate-induced oxidative injury of renal tubular cell and CaOx crystal depositions in the rat kidney via, at least in part, inhibiting the activation of p38 signaling pathway, thus representing a novel role of autophagy in the regulation of oxalate-induced renal oxidative injury and CaOx crystal depositions for the first time.

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“…Mammals express at least four distinctly regulated groups of MAPKs including extracellular signal‐related kinases (ERK)‐1/2, Jun amino‐terminal kinases (JNK1/2/3), p38MAPK proteins (p38MAPK has α/β/γ/δ isoforms) and ERK5 which are activated by specific upstream MAPK Kinases (MAPKKs, or MEKs). MAPK signalling activates at least 20 transcription factors, and is involved in a series of other signalling pathways …”

Section: Molecular Mechanismsmentioning

confidence: 99%

Cardiac fibrosis in the ageing heart: Contributors and mechanisms

Guo

Yue

et al. 2017

Clin Exp Pharma Physio

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Cardiac fibrosis refers to an excessive deposition of extracellular matrix (ECM) in cardiac tissue. Fibrotic tissue is stiffer and less compliant, resulting in subsequent cardiac dysfunction and heart failure. Cardiac fibrosis in the ageing heart may involve activation of fibrogenic signalling and inhibition of anti-fibrotic signalling, leading to an imbalance of ECM turnover. Excessive accumulation of ECM such as collagen in older patients contributes to progressive ventricular dysfunction. Overexpression of collagen is derived from various sources, including higher levels of fibrogenic growth factors, proliferation of fibroblasts and cellular transdifferentiation. These may be triggered by factors, such as oxidative stress, inflammation, hypertension, cellular senescence and cell death, contributing to age-related fibrotic cardiac remodelling. In this review, we will discuss the fibrogenic contributors in age-related cardiac fibrosis, and the potential mechanisms by which fibrogenic processes can be interrupted for therapeutic intent.

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p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells

Cited by 45 publications

References 52 publications

Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma

Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney

Cardiac fibrosis in the ageing heart: Contributors and mechanisms

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